CXCR4 mediated chemotaxis is regulated by 5T4 oncofetal glycoprotein in mouse embryonic cells

Thomas D. Southgate, Owen J. McGinn, Fernanda V. Castro, Andrzej J. Rutkowski, Mariam Al-Muftah, Georgi Marinov, Graeme J. Smethurst, David Shaw, Christopher M. Ward, Crispin J. Miller, Peter L. Stern

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

5T4 oncofetal molecules are highly expressed during development and upregulated in cancer while showing only low levels in some adult tissues. Upregulation of 5T4 expression is a marker of loss of pluripotency in the early differentiation of embryonic stem (ES) cells and forms an integrated component of an epithelial-mesenchymal transition, a process important during embryonic development and metastatic spread of epithelial tumors. Investigation of the transcriptional changes in early ES differentiation showed upregulation of CXCL12 and down-regulation of a cell surface protease, CD26, which cleaves this chemokine. CXCL12 binds to the widely expressed CXCR4 and regulates key aspects of development, stem cell motility and tumour metastasis to tissues with high levels of CXCL12. We show that the 5T4 glycoprotein is required for optimal functional cell surface expression of the chemokine receptor CXCR4 and CXCL12 mediated chemotaxis in differentiating murine embryonic stem cells and embryo fibroblasts (MEF). Cell surface expression of 5T4 and CXCR4 molecules is colocalized in differentiating ES cells and MEF. By contrast, differentiating ES and MEF derived from 5T4 knockout (KO) mice show only intracellular CXCR4 expression but infection with adenovirus encoding mouse 5T4 restores CXCL12 chemotaxis and surface co-localization with 5T4 molecules. A series of chimeric constructs with interchanged domains of 5T4 and the glycoprotein CD44 were used to map the 5T4 sequences relevant for CXCR4 membrane expression and function in 5T4KO MEF. These data identified the 5T4 transmembrane domain as sufficient and necessary to enable CXCR4 cell surface expression and chemotaxis. Furthermore, some monoclonal antibodies against m5T4 can inhibit CXCL12 chemotaxis of differentiating ES cells and MEF which is not mediated by simple antigenic modulation. Collectively, these data support a molecular interaction of 5T4 and CXCR4 occurring at the cell surface which directly facilitates the biological response to CXCL12. The regulation of CXCR4 surface expression by 5T4 molecules is a novel means to control responses to the chemokine CXCL12 for example during embryogenesis but can also be selected to advantage the spread of a 5T4 positive tumor from its primary site

Original languageEnglish
Article numbere9982
JournalPLoS One
Volume5
Issue number4
DOIs
Publication statusPublished - 10 Sep 2010
Externally publishedYes

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chemotaxis
Chemotaxis
embryonic stem cells
glycoproteins
Embryonic Stem Cells
Glycoproteins
Stem cells
mice
Chemokine CXCL12
neoplasms
Tumors
Embryonic Development
cells
Molecules
Neoplasms
Antigenic Modulation
Up-Regulation
embryogenesis
Adenoviridae Infections
stem form

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Southgate, T. D., McGinn, O. J., Castro, F. V., Rutkowski, A. J., Al-Muftah, M., Marinov, G., ... Stern, P. L. (2010). CXCR4 mediated chemotaxis is regulated by 5T4 oncofetal glycoprotein in mouse embryonic cells. PLoS One, 5(4), [e9982]. https://doi.org/10.1371/journal.pone.0009982

CXCR4 mediated chemotaxis is regulated by 5T4 oncofetal glycoprotein in mouse embryonic cells. / Southgate, Thomas D.; McGinn, Owen J.; Castro, Fernanda V.; Rutkowski, Andrzej J.; Al-Muftah, Mariam; Marinov, Georgi; Smethurst, Graeme J.; Shaw, David; Ward, Christopher M.; Miller, Crispin J.; Stern, Peter L.

In: PLoS One, Vol. 5, No. 4, e9982, 10.09.2010.

Research output: Contribution to journalArticle

Southgate, TD, McGinn, OJ, Castro, FV, Rutkowski, AJ, Al-Muftah, M, Marinov, G, Smethurst, GJ, Shaw, D, Ward, CM, Miller, CJ & Stern, PL 2010, 'CXCR4 mediated chemotaxis is regulated by 5T4 oncofetal glycoprotein in mouse embryonic cells', PLoS One, vol. 5, no. 4, e9982. https://doi.org/10.1371/journal.pone.0009982
Southgate, Thomas D. ; McGinn, Owen J. ; Castro, Fernanda V. ; Rutkowski, Andrzej J. ; Al-Muftah, Mariam ; Marinov, Georgi ; Smethurst, Graeme J. ; Shaw, David ; Ward, Christopher M. ; Miller, Crispin J. ; Stern, Peter L. / CXCR4 mediated chemotaxis is regulated by 5T4 oncofetal glycoprotein in mouse embryonic cells. In: PLoS One. 2010 ; Vol. 5, No. 4.
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